Advances in reciprocal regulation mechanisms of microRNAs and target genes

MicroRNAs (miRNAs), which are encoded by endogenous genes, are a class of single-stranded non-coding RNAs with approximately 22 nt in length. They act on target genes by binding to Argonaute (AGO) family proteins to form miRNA-induced silencing complexes (miRISCs), thereby functioning at the transcriptional and post-transcriptional levels. With the in-depth study of miRNAs, it has been found that in addition to messenger RNAs (mRNAs), non-coding RNAs (ncRNAs), primary miRNAs (pri-miRNAs), and DNAs can also act as the target genes of miRNAs. By mRNA or ncRNA cleavage, DNA transcription silence or activation, pri-miRNA processing, and mRNA translation, miRNAs regulate almost all cell proliferation/differentiation, individual growth/development, and homeostasis. Since miRNAs are differentially expressed in various cell types and play a role in the whole development process, studies on miRNAs have focused on their origins, biogenesis, and mechanisms. However, the mechanisms of miRNA transformation, especially the rapid change of miRNAs under specific conditions, have not been well addressed. Recently, it has been discovered that target genes can regulate the biogenesis, degradation, and protection of miRNAs in a sequence-dependent manner, indicating that the regulation of miRNAs and target genes is not unidirectional, but reciprocal. The target genes modulate the biogenesis of miRNAs by mediating the processing, stability, and nuclear export of pri-miRNAs or precursor miRNAs (pre-miRNAs). The modulation depends on the binding of miRNAs to the complementary sequence on the target genes. However, no general binding pattern represents the modulation of target genes on miRNA biogenesis. Extensive complementarity between target genes and miRNAs is a crucial requirement for the target-directed miRNA degradation (TDMD). Central bulge with varied length is a mismatched region in the center of an extensive complementarity and is essential to trigger TDMD. The mechanisms of TDMD are controversial. It may be due to the exonuclease-induced miRNA degradation, which is dependent on tailing and trimming; or the ZSWIM8 ubiquitin ligase-triggered miRNA degradation, which is independent of tailing and trimming. Organisms increase miRNA stability through target genes and coordinate with TDMD to maintain miRNA homeostasis. Elevated accumulation of the passenger strand in AGO is found in the process of target genes promoting miRNA stability. However, it is unclear whether the process will trigger a transformation of the guide strand. Although the study on the regulation of miRNAs by target genes is still in infancy, it provides a novel perspective for the regulation of miRNAs. In this review, the latest progress in the regulation of miRNAs by target genes was outlined in detail, the conditions, mechanisms, and functions of their interaction were summarized, and future research directions on miRNAs transformation were proposed in order to provide a theoretical basis for further understanding the interaction between miRNAs and target genes in vivo and the development of miRNA-based therapeutic approaches.